Schizophrenia is a severe psychiatric condition that affects approximately one percent of the population worldwide (Lewis, D. A. & Lieberman, J. A. (2000) Neuron 28, 325-3). The disease is characterized by a variety of so-called “positive” symptoms that tend to occur episodically, including hallucinations, delusions, paranoia, and psychosis and/or relatively persistent symptoms such as flattened affect, social withdrawal, impaired attention, and cognitive impairments. Symptoms in the latter category are frequently referred to as “negative symptoms”.
Studies of the inheritance of schizophrenia have revealed that it is a multi-factorial disease characterized by multiple genetic susceptibility elements, each likely contributing a modest increase in risk (Karayiorgou, M. & Gogos, J. A. (1997) Neuron 19, 967-79). Family linkage studies and studies of chromosomal abnormalities associated with schizophrenia have identified a number of schizophrenia susceptibility loci (Karayiorgou, M. & Gogos, J. A. (1997) Neuron 19, 967-79; Thaker, G. K. & Carpenter, W. T., Jr. (2001) Nat Med 7, 667-71). These loci encompass relatively large chromosomal regions and can contain hundreds of genes. Therefore, the identification of specific susceptibility genes in these regions is challenging.
In addition to direct genetic analysis, a longstanding body of pharmacological studies has led to the prevailing hypotheses that dysfunction of dopaminergic or NMDA receptor-mediated signaling are major contributing factors in schizophrenia pathogenesis (Seeman, P. (1987) Synapse 1, 133-52; Carlsson, A., et al., (2001) Annu Rev Pharmacol Toxicol 41, 237-60). The dopamine hypothesis for the pathophysiology of schizophrenia maintains that dysfunction of the dopamine neurotransmitter system plays a key role in the abnormalities that occur in schizophrenia. This hypothesis stems from the observation that many drugs effective in treating schizophrenia share the common property of blocking dopamine receptors. In addition, certain of the symptoms of schizophrenia can be reproduced by drugs such as amphetamine that act positively on the dopaminergic system. The glutamate dysfunction hypothesis provides an alternate, and not necessarily inconsistent potential explanation for the etiology of schizophrenia. This hypothesis arose from the observation that exposure to certain compounds such as phencyclidine (PCP) and MK-801, which act as antagonists of NMDA receptors (physiological receptors for glutamate), leads to development of schizophrenia-like symptoms. (See, e.g., Javitt, D. and Zukin, R., Am J Psychiatry, October 1991; 148(10):1301-8. Despite the appeal of these hypotheses, convincing direct genetic, physiological, or biochemical evidence for association of dopamine receptors or NMDA receptors with schizophrenia has not been obtained. In addition, although various pharmacological agents for the treatment of schizophrenia exist and are widely used, no truly satisfactory therapy exists.
Thus there remains a need in the art for improved understanding of the etiology of schizophrenia. In addition, there remains a need in the art for improved methods and reagents for the diagnosis and treatment of schizophrenia and susceptibility to schizophrenia.